NF-KAPPA-B-INDUCING KINASE ACTIVATES IKK-ALPHA BY PHOSPHORYLATION OF SER-176

Activation of the transcription factor NF-kappa B by inflammatory cyto kines involves the successive action of NF-kappa B-inducing kinase (NI K) and two I kappa B kinases, IKK-alpha and IKK-beta. Here we shaw tha t NIK preferentially phosphorylates IKK-alpha over IKK-beta, leading t o the activation of IKK-alpha kinase activity, This phosphorylation of IKK-alpha occurs specifically on Ser-176 in the activation loop betwe en kinase subdomains VII and VIII. A mutant form of IKK-alpha containi ng alanine at residue 176 cannot be phosphorylated or activated by NIK and acts as a dominant negative inhibitor of interleukin 1- and turne r necrosis factor-induced NF-kappa B activation, Conversely, a mutant form of IKK-alpha containing glutamic acid at residue 176 is constitut ively active, Thus, the phosphorylation of IKK-alpha on Scr-176 by NIK may be required for cytokine-mediated NF-kappa B activation.